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Purpose Dioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL , is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown. Methods We applied exome sequencing in a cohort of over 10,000 individuals with neurodevelopmental diseases. Effects of HPDL loss were investigated in vitro and in vivo, and through mass spectrometry analysis. Evolutionary analysis was performed to investigate the potential functional separation of HPDL from HPD. Results We identified biallelic variants in HPDL in eight families displaying recessive inheritance. Knockout mice closely phenocopied humans and showed evidence of apoptosis in multiple cellular lineages within the cerebral cortex. HPDL is a single-exonic gene that likely arose from a retrotransposition event at the base of the tetrapod lineage, and unlike HPD, HPDL is mitochondria-localized. Metabolic profiling of HPDL mutant cells and mice showed no evidence of altered tyrosine metabolites, but rather notable accumulations in other metabolic pathways. Conclusion The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.

Infantile neuroaxonal degeneration (INAD) is a rare subgroup of neurodegeneration with brain iron accumulation (NBIA) disorders. This progressive disorder may develop during the early years of life. Affected individuals mostly manifest developmental delay and/or psychomotor regression as well as other neurological deficits. In the present study, we discussed 3 INAD patients diagnosed before the age of 10 by using Whole-Exome Sequencing (WES). We evaluated 3 pediatric patients with clinical phenotypes of INAD who underwent WES. Sanger sequencing was performed for co-segregation analysis of the variants in the families. An study was conducted for identification of the molecular function of the identified genetic variants in the gene. We detected three novel genetic variants in the PLA2G6 gene including a homozygous missense (NM_003560.2; c.1949T>C; p.Phe650Ser), a splicing (NM_001349864; c.1266-1G>A) and a frameshift variant (NM_003560.4; c.1547_1548dupCG; p.Gly517ArgfsTer29). Since the variants were not previously reported in literature or population databases, we performed in-silico studies for these variants and demonstrated their potential pathogenicity. The current study reports novel genetic variants in the gene in the Iranian population, emphasizing the importance of high-throughput genetic testing in rare diseases.

We report a patient with complex clinical presentation including multiple neurological symptoms and eye involvement. Upon genetic investigation, the patient was found to carry a novel homozygous mutation in the NDUFS4 gene, thus adding to the heterogeneity of Leigh syndrome clinical presentation. We report a patient with complex clinical presentation including multiple neurological symptoms and eye involvement. Upon genetic investigation, the patient was found to carry a novel homozygous mutation in the NDUFS4 gene, thus adding to the heterogeneity of Leigh syndrome clinical presentation.

We describe a 3.5‐year‐old Iranian female child and her affected 10‐month‐old brother with a maternally inherited derivative chromosome 9 [der(9)]. The postnatally detected rearrangement was finely characterized by aCGH analysis, which revealed a 15.056 Mb deletion of 9p22.3‐p24.3p22.3 encompassing 14 OMIM morbid genes such as DOCK8, KANK1, DMRT1 and SMARCA2, and a gain of 3.309 Mb on 18p11.31‐p11.32 encompassing USP14, THOC1, COLEC12, SMCHD1 and LPIN2. We aligned the genes affected by detected CNVs to clinical and functional phenotypic features using PhenogramViz. In this regard, the patient's phenotype and CNVs data were entered into PhenogramViz. For the 9p deletion CNV, 53 affected genes were identified and 17 of them were matched to 24 HPO terms describing the patient's phenotypes. Also, for CNV of 18p duplication, 22 affected genes were identified and six of them were matched to 13 phenotypes. Moreover, we used DECIPHER for in‐depth characterization of involved genes in detected CNVs and also comparison of patient phenotypes with 9p and 18p genomic imbalances. Based on our filtration strategy, in the 9p22.3‐p24.3 region, approximately 80 pathogenic/likely pathogenic/uncertain overlapping CNVs were in DECIPHER. The size of these CNVs ranged from 12.01 kb to 18.45 Mb and 52 CNVs were smaller than 1 Mb in size affecting 10 OMIM morbid genes. The 18p11.31‐p11.32 region overlapped 19 CNVs in the DECIPHER database with the size ranging from 23.42 kb to 1.82 Mb. These CNVs affect eight haploinsufficient genes.

Background Zellweger spectrum disorders (ZSDs) are a group of peroxisome biogenesis disorders (PBDs) with different variants in the PEX genes. The main biochemical marker for screening peroxisomal disorders is very long-chain fatty acids (VLCFAs). The study reveals a rare case of PBD in the Zellweger spectrum in which she had normal plasma VLCFA levels. Case presentation Here, we report a 10-year-old girl with neurodevelopmental delay, facial dysmorphism, and hearing impairment. A brain magnetic resonance imaging scan was done to determine the reason for the seizures and neurodevelopmental delay. MRI images showed a mild widening in sulci especially in frontal lobes and sylvian fissures with pachygyria in the perisylvian regions. Biochemical analysis was done to detect ZSD. However, plasma VLCFA levels were normal. The diagnosis was made using whole-exome sequencing (WES). A homozygous variant of uncertain significance (VUS) in PEX6 NM_000287.4: c.1992G > C (p. Glu664Asp) was identified which has been confirmed through Sanger sequencing in probands and her parents. Conclusions According to the case report, plasma VLCFA levels can be normal in patients with PBDs in the Zellweger spectrum. Furthermore, we could re-classify the c.1992G > C variant in the PEX6 gene from VUS to likely pathogenic based on clinical manifestations including facial dysmorphism, and hearing impairment.

Objectives The current study devised a mindfulness intervention program, integrating face-to-face and group training with individualized technology-accessible practices. It aimed at investigating the role of Blended Mindfulness Intervention (BMI), which combines mainstream mindfulness practices with digital tools, in university students’ sustained attention, working memory, academic achievement, and electroencephalogram (EEG) asymmetry. Method Sixty junior university students, selected from a pool of 72 candidates, were randomly assigned into two groups. Mindfulness training (MT) was incorporated into class activities of experimental group in a course of eight sessions. The participants of experimental group were also assigned to do some weekly follow-up activities offered via a smartphone-based mindfulness meditation application (Smiling Mind). The homogeneity of the two groups was ascertained prior the study on mindfulness, working memory (determined via Automated Operation Span [AOSPAN] task), and sustained attention. The tripartite mindfulness instruction encompassed these activities: (1) in-class general MT practices, (2) in-class educational-inspired practices, and (3) at-home practices via Smiling Mind. Results The results of statistical analysis via independent samples t -tests verified the efficiency of BMI in enhancing university students’ sustained attention, working memory, and academic achievement. The analysis of EEG measurements via a 19-channel device demonstrated reduction in the theta/beta ratio (TBR) values in all brain regions, including frontal, parietal, occipital, and central in posttest. The ratio is a measure often used in EEG studies to assess brain activity. Conclusions This study substantiated that promoting state mindfulness in MT programs develops trait mindfulness, which brings about a host of cognitive, emotional, social, and metacognitive benefits. It also demonstrated that supplementing face-to-face and group interventions with individualized and easily accessible and affordable ones seem to cater for all styles and preferences and ultimately augment the efficiency of these programs. Preregistration This study is not preregistered.

Background Idiopathic intracranial hypertension (IIH) is a rare medical condition in children. Based on the different radiological findings reported in various studies in pediatric IIH, this study was conducted to determine the diagnostic value of MRI findings in diagnosing IIH in children. Methods In this retrospective study, the medical records of all children aged 1 to 18 years who visited Ghaem Hospital in Mashhad, Iran, between 2012 and 2022 and were diagnosed with IIH were gathered. Forty-nine cases of children with IIH and 48 control cases of children with the first unprovoked seizure with no indications of increased intracranial pressure for comparison were selected. Patient demographic information and MRI findings were extracted. The comparison between different MRI findings in the case and control groups was conducted using statistical tests. Results In the case group, the mean diameter of the subarachnoid space expansion around the optic nerve was 5.96 ± 1.21, compared to 4.79 ± 0.33 in the control group, with statistically significant difference ( P  < 0.001). All the patients with flattening of the posterior globe or transverse sinus stenosis were in the case group, and the frequency of these findings in the case group was significantly higher than in the control group ( P  < 0.001). The majority of patients (95.5%) classified under category 3 and 4 of empty sella were part of the case group, and the statistical test results indicated a significant difference between the two groups ( P  < 0.001). The optic nerve sheath diameter cut-off of 5.35 mm, when used for expansion of the subarachnoid space around the optic nerve, with a sensitivity of 82% and a specificity of 100% in diagnosing IIH. Conclusion The most reliable diagnostic indicators for diagnosing IIH in children are perioptic subarachnoid space expansion with high sensitivity, and posterior globe flattening and transverse sinus stenosis with high specificity.

Background Designing an upper extremity neurorehabilitation protocol for children with unilateral cerebral palsy (UCP) is a significant challenge. In this study, a combined rehabilitation protocol is proposed for restoring upper extremity function in children with unilateral cerebral palsy. Methods The proposed protocol combines mechanical stimulation of cutaneous mechanoreceptors on the back of the affected hand with computer game-based training. Drawing on insights into neural self-organization, a chaotic model was identified and utilized to generate the stimulation pattern. The efficacy of the proposed approach was evaluated in four patients. Results The results were analyzed across various clinical and signal-processing aspects. The clinical findings are promising, demonstrating intriguing improvement in wrist flexion and extension motion following the interventions. Additionally, nonlinear analyses of EMG dynamics and muscle activation timings suggest that the creation of a new motor program post-intervention is plausible. Conclusion Clinical analyses and nonlinear analysis of EMG dynamics supported the emergence of neuroplasticity following the designed rehabilitation protocol.

Background Phospholipase-associated neurodegeneration (PLAN) caused by mutations in the PLA2G6 gene is a rare neurodegenerative disorder that presents with four sub-groups. Infantile neuroaxonal dystrophy (INAD) and PLA2G6 -related dystonia-parkinsonism are the main two subtypes. In this cohort, we reviewed clinical, imaging, and genetic features of 25 adult and pediatric patients harboring variants in the PLA2G6 . Methods An extensive review of the patients’ data was carried out. Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS) was used for evaluating the severity and progression of INAD patients. Whole-exome sequencing was used to determine the disease's underlying etiology followed by co-segregation analysis using Sanger sequencing. In silico prediction analysis based on the ACMG recommendation was used to assess the pathogenicity of genetic variants. We aimed to survey a genotype-genotype correlation in PLA2G6 considering all reported disease-causing variants in addition to our patients using the HGMD database and the chi-square statistical approach. Results Eighteen cases of INAD and 7 cases of late-onset PLAN were enrolled. Among 18 patients with INAD, gross motor regression was the most common presenting symptom. Considering the INAD-RS total score, the mean rate of progression was 0.58 points per month of symptoms (Standard error 0.22, lower 95% − 1.10, and upper 95% − 0.15). Sixty percent of the maximum potential loss in the INAD-RS had occurred within 60 months of symptom onset in INAD patients. Among seven adult cases of PLAN, hypokinesia, tremor, ataxic gate, and cognitive impairment were the most frequent clinical features. Various brain imaging abnormalities were also observed in 26 imaging series of these patients with cerebellar atrophy being the most common finding in more than 50%. Twenty unique variants in 25 patients with PLAN were detected including nine novel variants. Altogether, 107 distinct disease-causing variants from 87 patient were analyzed to establish a genotype–phenotype correlation. The P value of the chi-square test did not indicate a significant relationship between age of disease onset and the distribution of reported variants on PLA2G6 . Conclusion PLAN presents with a wide spectrum of clinical symptoms from infancy to adulthood. PLAN should be considered in adult patients with parkinsonism or cognition decline. Based on the current knowledge, it is not possible to foresee the age of disease onset based on the identified genotype.

Major Facilitator Superfamily Domain containing 2a (MFSD2A) is an essential endothelial lipid transporter at the blood-brain barrier. Biallelic variants affecting function in MFSD2A cause autosomal recessive primary microcephaly 15 (MCPH15, OMIM# 616486). We sought to expand our knowledge of the phenotypic spectrum of MCPH15 and demonstrate the underlying mechanism of inactivation of the MFSD2A transporter. We carried out detailed analysis of the clinical and neuroradiological features of a series of 27 MCPH15 cases, including eight new individuals from seven unrelated families. Genetic investigation was performed through exome sequencing (ES). Structural insights on the human Mfsd2a model and in-vitro biochemical assays were used to investigate the functional impact of the identified variants. All patients had primary microcephaly and severe developmental delay. Brain MRI showed variable degrees of white matter reduction, ventricular enlargement, callosal hypodysgenesis, and pontine and vermian hypoplasia. ES led to the identification of six novel biallelic MFSD2A variants (NG_053084.1, NM_032793.5: c.556+1G>A, c.748G>T; p.(Val250Phe), c.750_753del; p.(Cys251SerfsTer3), c.977G>A; p.(Arg326His), c.1386_1435del; p.(Gln462HisfsTer17), and c.1478C>T; p.(Pro493Leu)) and two recurrent variants (NM_032793.5: c.593C>T; p.(Thr198Met) and c.476C>T; p.(Thr159Met)). All these variants and the previously reported NM_032793.5: c.490C>A; p.(Pro164Thr) resulted in either reduced MFSD2A expression and/or transport activity. Our study further delineates the phenotypic spectrum of MCPH15, refining its clinical and neuroradiological characterization and supporting that MFSD2A deficiency causes early prenatal brain developmental disruption. We also show that poor MFSD2A expression despite normal transporter activity is a relevant pathomechanism in MCPH15.